IQUIBICEN   23947
INSTITUTO DE QUIMICA BIOLOGICA DE LA FACULTAD DE CIENCIAS EXACTAS Y NATURALES
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Transcriptome analysis of childhood Acute Lymphoblastic Leukemia samples revealed that disease outcome might be associated with the dysregulation of several non-coding RNAs.
Autor/es:
ABBATE, MERCEDES; ALONSO, MARTA; AVERSA, LUIS; COTIGNOLA, JAVIER; ORELLANO, LAURA; GUTIERREZ, MARCELA; VAZQUEZ, ELBA; RICCHERI, CECILIA; GUIÑAZU, KARINA; SCHUTTENBERG, VIRGINIA
Lugar:
Helsinki
Reunión:
Congreso; 11th Biennial Childhood Leukemia and Lymphoma Symposium; 2018
Institución organizadora:
Nordic Society of Paediatric Haematology and Oncology
Resumen:
Patients diagnosed with Acute Lymphoblastic Leukemia (ALL) are stratified into risk groups according to biochemical parameters, cytogenetic and molecular signatures, and the early response to therapy. Although huge progress in treatment efficacy and survival rates was achieved for childhood ALL, disease outcome is still unpredictable in many cases. One promising strategy to better understand the biology of childhood ALL is to study the transcriptome of leukemic cells in order to identify gene expression profiles driving the outcome. One example highlighting the importance of these type of studies is the documentation of the Philadelphia chromosome?like ALL that is characterized by a gene expression profile similar to that of Phi+, even though the BCR-ABL1 fusion protein is absent.In the present study, we sought to identify gene expression profiles that predict childhood ALL outcome and acute therapy-related toxicity. To accomplish this, we collected samples by bone marrow aspiration at time of diagnosis. Total RNA was purified using the TRIZOL protocol. We performed paired-end transcriptome analysis (RNAseq) from 29 pediatric patients with de-novo ALL using a HiSeq 2500 System (Illumina). Clinico-pathological characteristics were evaluated and recorded by trained oncohematologists. We performed differential gene expression analysis between risk groups, presence of relapse and acute grade-3/4 toxicity. We considered that genes were differentially expressed if the FDR adjusted p-value≤0.05. Because relapse and toxicity might be associated with the risk group, and consequently with treatment protocols, we carried out multivariate analyses including the risk group as a covariate for relapse and toxicity.We found 5 Differentially Expressed Genes (DEG) between high risk (n=5) and intermediate risk (n=19) patients. Interestingly, one of the most dysregulated genes was one long intergenic non-coding RNA (Log2FC=-20, adj. p-value=0.02). When we compared patient with (n=4) and without (n=20) relapse, we detected 40 DEG. The adjusted p-values ranged between 0.05 and 10-14, and the Log2FC ranged from 2 to 30. Surprisingly, 42.5% (17/40) of the DEG were non-conding RNAs (ncRNAs): 59% (10/17) were strongly downregulated (Log2FC≤-16) and the rest were moderate to highly upregulated (Log2FC=3-9). Finally, we analyzed the transcriptome of patients with (n=3) and without (n=11) acute grade-3/4 toxicity. We identified 33 DEG with Log2FC=5-30 (adj. p-values=0.05-6.6x10-8). In this case, 12% of the DEG were ncRNA and all of them were highly upregulated (Log2FC≥21).The human genome contains about 20,000 protein-coding genes, representing 2% of the genome. Historically, the other 98% of the genome was referred as ?junk DNA?. However, there is now robust emerging evidence that about 85% of the genome can be transcribed and that approximately half of disease- and trait-associated genomic regions are intergenic. These non-protein-coding regions are transcribed to ncRNA, which are known to be key regulators of the transcriptional and translational repertoire of the cell. Moreover, there are solid proofs that alterations of these ncRNAs are highly associated with tumor development and progression. In conclusion, dysregulation of ncRNAs is a common feature in childhood ALL outcome. The detection of differential expressed ncRNAs might help to improve childhood ALL prognosis and identify new potential therapeutic targets.